tbuckley/cabot-search huggingface dataset:
Efficacy and immunogenicity of R21/Matrix-M vaccine against clinical malaria after 2 years' follow-up in children in Burkina Faso: a phase 1/2b randomised controlled trial
Authors: Mehreen S Datoo, Hamtandi Magloire Natama, Athanase Somé, Duncan Bellamy, Ousmane Traoré, Toussaint Rouamba, Marc Christian Tahita, N Félix André Ido, Prisca Yameogo, Daniel Valia, Aida Millogo, Florence Ouedraogo, Rachidatou Soma, Seydou Sawadogo, Faizatou Sorgho, Karim Derra, Eli Rouamba, Fernando Ramos-Lopez, Matthew Cairns, Samuel Provstgaard-Morys, Jeremy Aboagye, Alison Lawrie, Rachel Roberts, Innocent Valéa, Hermann Sorgho, Nicola Williams, Gregory Glenn, Louis Fries, Jenny Reimer, Katie J Ewer, Umesh Shaligram, Adrian V S Hill, Halidou Tinto
Journal: The Lancet Infectious Diseases (2022)
Long term mental health trajectories after disasters and pandemics: A multilingual systematic review of prevalence, risk and protective factors
Authors: Elizabeth A. Newnham, Enrique L.P. Mergelsberg, Yanyu Chen, Yoshiharu Kim, Lisa Gibbs, Peta L. Dzidic, Makiko Ishida DaSilva, Emily Y.Y. Chan, Kanji Shimomura, Zui Narita, Zhe Huang, Jennifer Leaning
Journal: Clinical Psychology Review (2022)
The 2022 monkeypox outbreak and associated psychiatric morbidities
Authors: Sirwan Khalid Ahmed, AbdulRahman A. Saied, Ramya Kundayi Ravi, Mona Gamal Mohammed, Safin Hassan Hussein, Rawand Abdulrahman Essa, Salar Omar Abdulqadir, Araz Qadir Abdulla
Journal: International Journal of Surgery (2022)
Elraglusib (9-ING-41), a selective small-molecule inhibitor of glycogen synthase kinase-3 beta, reduces expression of immune checkpoint molecules PD-1, TIGIT and LAG-3 and enhances CD8+ T cell cytolytic killing of melanoma cells
Authors: Gary Shaw, Ludimila Cavalcante, Francis J. Giles, Alison Taylor
Journal: Journal of Hematology & Oncology (2022)

Abstract Background Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with multiple roles in tumour growth, cell invasion and metastasis. We have previously established GSK-3 as an upstream regulator of PD-1 gene expression in CD8 + T cells and demonstrated that GSK-3 inhibition is as effective as anti-PD-1 mAb blockade in controlling tumour growth. Elraglusib (9-ING-41) is a specific small-molecule inhibitor of GSK-3β with clinical activity in patients with advanced cancers, including a patient with refractory melanoma whose response provided the rationale for the current study. Methods The B16 melanoma mouse model was used to observe the effect of elraglusib on tumour growth either as a single agent or in combination (simultaneously and sequentially) with anti-PD-1 mAb treatment. B16 tumour cells were implanted in either the flank, brain or both locations, and Kaplan–Meier plots were used to depict survival and significance determined using log rank tests. Expression of the immune checkpoint molecules, TIGIT, LAG-3 and PD-1, was evaluated using flow cytometry alongside expression of the chemokine receptor, CXCR3. Further evaluation of PD-1 expression was determined through RT-qPCR and immunohistochemistry. Results We demonstrated that elraglusib has a suppressive effect against melanoma as a single agent and enhanced anti-PD-1 therapy. There was a synergistic effect when elraglusib was used in combination with anti-PD-1 mAb, and an even greater effect when used as sequential therapy. Suppression of tumour growth was associated with a reduced expression of immune checkpoint molecules, PD-1, TIGIT and LAG-3 with upregulation of CXCR3 expression. Conclusions These data highlight the potential of elraglusib as an immune-modulatory agent and demonstrate the benefit of a sequential approach with immune checkpoint inhibition followed by GSK-3β inhibition in melanoma and provide a rationale for clinical investigation of elraglusib combined with immune checkpoint inhibitory molecules, including those targeting PD-1, TIGIT and LAG-3. This has several potential implications for current immunotherapy regimes, including possibly reducing the intensity of anti-PD-1 mAb treatment needed for response in patients receiving elraglusib, especially given the benign adverse event profile of elraglusib observed to date. Based on these data, a clinical study of elraglusib, an anti-PD-1 mAb and chemotherapy is ongoing (NCT NCT05239182).
Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial
Authors: M. Fish, J. Rynne, A. Jennings, C. Lam, A. A. Lamikanra, J. Ratcliff, S. Cellone-Trevelin, E. Timms, J. Jiriha, I. Tosi, R. Pramanik, P. Simmonds, S. Seth, J. Williams, A. C. Gordon, J. Knight, D. J. Smith, J. Whalley, D. Harrison, K. Rowan, H. Harvala, P. Klenerman, L. Estcourt, D. K. Menon, D. Roberts, M. Shankar-Hari
Journal: Intensive Care Medicine (2022)
Prolonged, Low-Level Exposure to the Marine Toxin, Domoic Acid, and Measures of Neurotoxicity in Nonhuman Primates
Authors: Rebekah L. Petroff, Christopher Williams, Jian-Liang Li, James W. MacDonald, Theo K. Bammler, Todd Richards, Christopher N. English, Audrey Baldessari, Sara Shum, Jing Jing, Nina Isoherranen, Brenda Crouthamel, Noelle McKain, Kimberly S. Grant, Thomas M. Burbacher, G. Jean Harry
Journal: Environmental Health Perspectives (2022)

The excitotoxic molecule, domoic acid (DA), is a marine algal toxin known to induce overt hippocampal neurotoxicity. Recent experimental and epidemiological studies suggest adverse neurological effects at exposure levels near the current regulatory limit (20 ppm, ∼0.075-0.1mg/kg). At these levels, cognitive effects occur in the absence of acute symptoms or evidence of neuronal death.This study aimed to identify adverse effects on the nervous system from prolonged, dietary DA exposure in adult, female Macaca fascicularis monkeys.Monkeys were orally exposed to 0, 0.075, and 0.15mg/kg per day for an average of 14 months. Clinical blood counts, chemistry, and cytokine levels were analyzed in the blood. In-life magnetic resonance (MR) imaging assessed volumetric and tractography differences in and between the hippocampus and thalamus. Histology of neurons and glia in the fornix, fimbria, internal capsule, thalamus, and hippocampus was evaluated. Hippocampal RNA sequencing was used to identify differentially expressed genes. Enrichment of gene networks for neuronal health, excitotoxicity, inflammation/glia, and myelin were assessed with Gene Set Enrichment Analysis.Clinical blood counts, chemistry, and cytokine levels were not altered with DA exposure in nonhuman primates. Transcriptome analysis of the hippocampus yielded 748 differentially expressed genes (fold change≥1.5; p≤0.05), reflecting differences in a broad molecular profile of intermediate early genes (e.g., FOS, EGR) and genes related to myelin networks in DA animals. Between exposed and control animals, MR imaging showed comparable connectivity of the hippocampus and thalamus and histology showed no evidence of hypomyelination. Histological examination of the thalamus showed a larger microglia soma size and an extension of cell processes, but suggestions of a GFAP+astrocyte response showed no indication of astrocyte hypertrophy.In the absence of overt hippocampal excitotoxicity, chronic exposure of Macaca fascicularis monkeys to environmentally relevant levels of DA suggested a subtle shift in the molecular profile of the hippocampus and the microglia phenotype in the thalamus that was possibly reflective of an adaptive response due to prolonged DA exposure. https://doi.org/10.1289/EHP10923.
Mortality Associated with Ambient PM2.5 Exposure in India: Results from the Million Death Study
Authors: Patrick E. Brown, Yurie Izawa, Kalpana Balakrishnan, Sze Hang Fu, Joy Chakma, Geetha Menon, Rajesh Dikshit, R.S. Dhaliwal, Peter S. Rodriguez, Guowen Huang, Rehana Begum, Howard Hu, George D’Souza, Randeep Guleria, Prabhat Jha
Journal: Environmental Health Perspectives (2022)

Background: Studies on the extent to which long-term exposure to ambient particulate matter (PM) with aerodynamic diameter ≤2.5μm (PM2.5) contributes to adult mortality in India are few, despite over 99% of Indians being exposed to levels that the World Health Organization (WHO) considers unsafe. Objective: We conducted a retrospective cohort study within the Million Death Study (MDS) to provide the first-ever quantification of national mortality from exposure to PM2.5 in India from 1999 to 2014. Methods: We calculated relative risks (RRs) by linking a total of ten 3-y intervals of satellite-based estimated PM2.5 exposure to deaths 3 to 5 y later in over 7,400 small villages or urban blocks covering a total population of 6.8 million. We applied using a model-based geostatistical model, adjusted for individual age, sex, and year of death; smoking prevalence, rural/urban residency, area-level female illiteracy, languages, and spatial clustering and unit-level variation. Results: PM2.5 exposure levels increased from 1999 to 2014, particularly in central and eastern India. Among 212,573 deaths at ages 15–69 y, after spatial adjustment, we found a significant RR of 1.09 [95% credible interval (CI): 1.04, 1.14] for stroke deaths per 10-μg/m3 increase in PM2.5 exposure, but no significant excess for deaths from chronic respiratory disease and ischemic heart disease (IHD), all nonaccidental causes, and total mortality (after excluding stroke). Spatial adjustment attenuated the RRs for chronic respiratory disease and IHD but raised those for stroke. The RRs were consistent in various sensitivity analyses with spatial adjustment, including stratifying by levels of solid fuel exposure, by sex, and by age group, addition of climatic variables, and in supplementary case–control analyses using injury deaths as controls. Discussion: Direct epidemiological measurements, despite inherent limitations, yielded associations between mortality and long-term PM2.5 inconsistent with those reported in earlier models used by the WHO to derive estimates of PM2.5 mortality in India. The modest RRs in our study are consistent with near or null mortality effects. They suggest suitable caution in estimating deaths from PM2.5 exposure based on MDS results and even more caution in extrapolating model-based associations of risk derived mostly from high-income countries to India. https://doi.org/10.1289/EHP9538
Comparison of State-Level Regulations for Cannabis Contaminants and Implications for Public Health
Authors: Laura E. Jameson, Kendra D. Conrow, Dorina V. Pinkhasova, Haleigh L. Boulanger, Hyunji Ha, Negar Jourabchian, Steven A. Johnson, Michael P. Simeone, Iniobong A. Afia, Thomas M. Cahill, Cindy S. Orser, Maxwell C.K. Leung
Journal: Environmental Health Perspectives (2022)

Background: The presence of contaminants in cannabis presents a potential health hazard to recreational users and susceptible patients with medical conditions. Because of the federally illegal status of cannabis, there are no unified regulatory guidelines mitigating the public health risk of cannabis contaminants. Objective: To inform further research and provide solutions to the public health risk of cannabis contaminants at a national level, we examined the current landscape of state-level contaminant regulations, and cannabis contaminants of concern, as well as patient populations susceptible to contaminants. Methods: We examined the regulatory documents for medical and recreational cannabis in all legalized U.S. jurisdictions and compiled a complete list of regulated contaminants, namely, pesticides, inorganics, solvents, microbes, and mycotoxins. We data mined the compliance testing records of 5,654 cured flower and 3,760 extract samples that accounted for ∼6% of California's legal cannabis production in 2020–2021. We also reviewed the publicly available medical cannabis use reports to tabulate the susceptible patient populations. Results: As of 18 May 2022, 36 states and the District of Columbia listed a total of 679 cannabis contaminants as regulated in medical or recreational cannabis, including 551 pesticides, 74 solvents, 12 inorganics, 21 microbes, 5 mycotoxins, and 16 other contaminants. Different jurisdictions showed significant variations in regulated contaminants and action levels ranging up to four orders of magnitude. A failure rate of 2.3% was identified for flowers and 9.2% for extracts in the California samples. Insecticides and fungicides were the most prevalent categories of detected contaminants, with boscalid and chlorpyrifos being the most common. The contaminant concentrations fell below the regulatory action levels in many legalized jurisdictions, indicating a higher risk of contaminant exposure. Cannabis use reports indicated usage in several patient populations susceptible to contamination toxicity, including cancer (44,318) and seizure (21,195) patients. Discussion: Although individual jurisdictions can implement their policies and regulations for legalized cannabis, this study demonstrates the urgent need to mitigate the public health risk of cannabis contamination by introducing national-level guidelines based on conventional risk assessment methodologies and knowledge of patients' susceptibility in medical use. https://doi.org/10.1289/EHP11206
METTL1-Mediated m7G tRNA Modification Promotes Lenvatinib Resistance in Hepatocellular Carcinoma
Authors: Manling Huang, Jianting Long, Zhijia Yao, Yi Zhao, Yutong Zhao, Junbin Liao, Kai Lei, Han Xiao, Zihao Dai, Sui Peng, Shuibin Lin, Lixia Xu, Ming Kuang
Journal: Cancer Research (2022)

Abstract The tyrosine kinase inhibitor lenvatinib is a first-line drug for treating patients with advanced hepatocellular carcinoma (HCC). However, its efficacy is severely hampered by drug resistance. Insights into the molecular mechanisms underlying lenvatinib resistance could provide new strategies to improve and prolong responses. Here, we performed unbiased proteomic screening of parental and lenvatinib-resistant HCC cells and discovered that methyltransferase-like protein-1 (METTL1) and WD repeat domain 4 protein (WDR4), the two key components of the tRNA N7-methylguanosine (m7G) methyltransferase complex, were dramatically upregulated in lenvatinib-resistant cells. METTL1 knockdown overrode resistance by impairing the proliferation capacity of HCC cells and promoting apoptosis under lenvatinib treatment. In addition, overexpression of wild-type METTL1 but not its catalytic dead mutant induced lenvatinib resistance. Animal experiments including hydrodynamic injection, subcutaneous implantation, and orthotopic xenograft mouse models further demonstrated the critical function of METTL1/WDR4-mediated m7G tRNA modification in promoting lenvatinib resistance in vivo. Mechanistically, METTL1 promoted translation of EGFR pathway genes to trigger drug resistance. This work reveals the important role of METTL1-mediated m7G tRNA modification in promoting lenvatinib resistance and provides a promising prediction marker and intervention target for resistance. Significance: Upregulation of tRNA m7G methyltransferase complex components METTL1 and WDR4 promotes lenvatinib resistance in HCC and confers a sensitivity to METTL1 targeting, providing a promising strategy to override resistance.
Medical Costs Associated With Diabetes Complications in Medicare Beneficiaries Aged 65 Years or Older With Type 2 Diabetes
Authors: Yu Wang, Ping Zhang, Hui Shao, Linda J. Andes, Giuseppina Imperatore
Journal: Diabetes Care (2022)

OBJECTIVE To estimate medical costs associated with 17 major diabetes-related complications and treatment procedures among Medicare beneficiaries aged ≥65 years with type 2 diabetes. RESEARCH DESIGN AND METHODS Claims data from 100% of Medicare beneficiaries enrolled in fee-for-service plans from 2006 to 2017 were analyzed. Records with type 2 diabetes and complications were identified using ICD-9, ICD-10, and diagnosis-related group codes. The index year was the year when a person was first identified as having diabetes with an inpatient claim or an outpatient claim plus another inpatient/outpatient claim in the 2 years following the first claim in Medicare. Included individuals were followed from index years until death, discontinuation of plan coverage, or 31 December 2017. Fixed-effects regression was used to estimate the cost in years when the complication event occurred and in subsequent years. The total cost for each complication was calculated for 2017 by multiplying the complication prevalence by the cost estimate. All costs were standardized to 2017 U.S. dollars. RESULTS Our study included 10,982,900 beneficiaries with type 2 diabetes. Follow-up ranged from 3 to 10 years. The three costliest complications were kidney failure treated by transplant (occurring year $79,045, subsequent years $17,303), kidney failure treated by dialysis ($54,394, $38,670), and lower-extremity amputation ($38,982, $8,084). Congestive heart failure accounted for the largest share (18%) of total complication costs. CONCLUSIONS Costs associated with diabetes complications were substantial. Our cost estimates provide essential information needed for conducting economic evaluation of treatment and programs to prevent and delay diabetes complications in Medicare beneficiaries.
Discrete-time survival analysis in the critically ill: a deep learning approach using heterogeneous data
Authors: Hans-Christian Thorsen-Meyer, Davide Placido, Benjamin Skov Kaas-Hansen, Anna P. Nielsen, Theis Lange, Annelaura B. Nielsen, Palle Toft, Jens Schierbeck, Thomas Strøm, Piotr J. Chmura, Marc Heimann, Kirstine Belling, Anders Perner, Søren Brunak
Journal: npj Digital Medicine (2022)

Prediction of survival for patients in intensive care units (ICUs) has been subject to intense research. However, no models exist that embrace the multiverse of data in ICUs. It is an open question whether deep learning methods using automated data integration with minimal pre-processing of mixed data domains such as free text, medical history and high-frequency data can provide discrete-time survival estimates for individual ICU patients. We trained a deep learning model on data from patients admitted to ten ICUs in the Capital Region of Denmark and the Region of Southern Denmark between 2011 and 2018. Inspired by natural language processing we mapped the electronic patient record data to an embedded representation and fed the data to a recurrent neural network with a multi-label output layer representing the chance of survival at different follow-up times. We evaluated the performance using the time-dependent concordance index. In addition, we quantified and visualized the drivers of survival predictions using the SHAP methodology. We included 37,355 admissions of 29,417 patients in our study. Our deep learning models outperformed traditional Cox proportional-hazard models with concordance index in the ranges 0.72-0.73, 0.71-0.72, 0.71, and 0.69-0.70, for models applied at baseline 0, 24, 48, and 72 h, respectively. Deep learning models based on a combination of entity embeddings and survival modelling is a feasible approach to obtain individualized survival estimates in data-rich settings such as the ICU. The interpretable nature of the models enables us to understand the impact of the different data domains.
WNT5A–RHOA Signaling Is a Driver of Tumorigenesis and Represents a Therapeutically Actionable Vulnerability in Small Cell Lung Cancer
Authors: Kee-Beom Kim, Dong-Wook Kim, Youngchul Kim, Jun Tang, Nicole Kirk, Yongyu Gan, Bongjun Kim, Bingliang Fang, Jae-ll Park, Yi Zheng, Kwon-Sik Park
Journal: Cancer Research (2022)

Abstract WNT signaling represents an attractive target for cancer therapy due to its widespread oncogenic role. However, the molecular players involved in WNT signaling and the impact of their perturbation remain unknown for numerous recalcitrant cancers. Here, we characterize WNT pathway activity in small cell lung cancer (SCLC) and determine the functional role of WNT signaling using genetically engineered mouse models. β-Catenin, a master mediator of canonical WNT signaling, was dispensable for SCLC development, and its transcriptional program was largely silenced during tumor development. Conversely, WNT5A, a ligand for β-catenin–independent noncanonical WNT pathways, promoted neoplastic transformation and SCLC cell proliferation, whereas WNT5A deficiency inhibited SCLC development. Loss of p130 in SCLC cells induced expression of WNT5A, which selectively increased Rhoa transcription and activated RHOA protein to drive SCLC. Rhoa knockout suppressed SCLC development in vivo, and chemical perturbation of RHOA selectively inhibited SCLC cell proliferation. These findings suggest a novel requirement for the WNT5A–RHOA axis in SCLC, providing critical insights for the development of novel therapeutic strategies for this recalcitrant cancer. This study also sheds light on the heterogeneity of WNT signaling in cancer and the molecular determinants of its cell-type specificity. Significance: The p130–WNT5A–RHOA pathway drives SCLC progression and is a potential target for the development of therapeutic interventions and biomarkers to improve patient treatment.
HDAC5 Loss Enhances Phospholipid-Derived Arachidonic Acid Generation and Confers Sensitivity to cPLA2 Inhibition in Pancreatic Cancer
Authors: Penglin Pan, Gengdu Qin, Bo Wang, Haixin Yu, Jie Chen, Jiaying Liu, Kaijian Bing, Jian Shen, Dianyun Ren, Yuhan Zhao, Wentao Xia, Hui Li, Heshui Wu, Yingke Zhou
Journal: Cancer Research (2022)

Abstract HDAC5 is a class IIa histone deacetylase member that is downregulated in multiple solid tumors, including pancreatic cancer, and loss of HDAC5 is associated with unfavorable prognosis. In this study, assessment of The Cancer Genome Atlas pancreatic adenocarcinoma dataset revealed that expression of HDAC5 correlates negatively with arachidonic acid (AA) metabolism, which has been implicated in inflammatory responses and cancer progression. Nontargeted metabolomics analysis revealed that HDAC5 knockdown resulted in a significant increase in AA and its downstream metabolites, such as eicosanoids and prostaglandins. HDAC5 negatively regulated the expression of the gene encoding calcium-dependent phospholipase A2 (cPLA2), the key enzyme in the production of AA from phospholipids. Mechanistically, HDAC5 repressed cPLA2 expression via deacetylation of GATA1. HDAC5 knockdown in cancer cells enhanced sensitivity to genetic or pharmacologic inhibition of cPLA2 in vitro and in vivo. Fatty acid supplementation in the diet reversed the sensitivity of HDAC5-deficient tumors to cPLA2 inhibition. These data indicate that HDAC5 loss in pancreatic cancer results in the hyperacetylation of GATA1, enabling the upregulation of cPLA2, which contributes to overproduction of AA. Dietary management plus cPLA2-targeted therapy could serve as a viable strategy for treating HDAC5-deficient pancreatic cancer patients. Significance: The HDAC5-GATA1-cPLA2-AA signaling axis regulates sensitivity to fat restriction plus cPLA2 inhibition in pancreatic ductal adenocarcinoma, proposing dietary management as a feasible strategy for treating a subset of patients with pancreatic cancer.
Commercially Available Insulin Products Demonstrate Consistency With Product Labeling Throughout All Seasons in the U.S.
Authors: Timothy J. Garrett, Sina Feizbakhsh Bazargani, Taylor Harmon, Jordan Kruse, Philip Atkinson, Eoin P. Quinlivan, Lynn Ang, Irl B. Hirsch, Lori Laffel, Massimo Pietropaolo, Michael J. Haller, Mark A. Atkinson
Journal: Diabetes Care (2022)
Pathophysiology. Altered Regulatory Mechanisms in Disease.
Journal: Annals of Internal Medicine (1972)

Book reviews abnormal whereas they are probably artefactual.The appearance of an in- nervated motor end-plate in 'denervated' muscle (plate 65) is puzzling.The bibliography is useful and includes references to work on experimental animal as well as human muscle.Although this book will not help the reader to understand the significance of the abnormalities illus- trated and makes no attempt to explain their pathogenesis it should be of interest to those involved in the study of muscle.